Fetal alcohol syndrome (FAS), the leading known cause of mental retardation in the Western world, has increased in incidence to 1.95/1000 live births, and 43.1/1000 live births among chronic alcoholics. While much research has focused on determining mechanisms underlying the teratogenicity of ethanol, the possibility that regulators of programmed cell death (PCD) may be involved in ethanol neurotoxicity and FAS has not been explored. The proposed experiments are based on the differential temporal susceptibility of cerebellar neurons to ethanol neurotoxicity; studies from a variety of laboratories have demonstrated that P4-5 is a time of susceptibility to ethanol, while P7-8 is a time of invulnerability. The following hypothesis will be explored: alterations in the levels of bc1-2 family PCD molecules contribute to the cerebellum's relative temporal susceptibility to ethanol. Rats will be exposed to ethanol in the first postnatal week, from postnatal day 4-5 (P4-5) or in the second post natal week, from P7-8. mRNA transcript levels of PCD repressor (bc1-2, bc1-x1 and PCD effector (bc1-xs, bax) genes will be quantitated by RNase protection assay and compared in ethanol-exposed and control groups for the two exposure paradigms. Anatomical studies will be carried out in parallel to ensure that cerebellar cells are exhibiting the expected temporal susceptibility to ethanol. Thus, the proposed studies will address the relationship between the differential temporal susceptibility of cerebellar neurons to ethanol and alterations in the levels of mRNAs of particular PCD molecules.